Cell-cell adhesion plays an important role in the development and in the function of adult tissues. Our characterization of the neural cell adhesion molecule, N-CAM, and the liver cell adhesion molecule, L-CAM, provided the first detailed description of cell adhesion molecules (CAMs) and their genes. These primary CAMs are both found in early embryonic cells and on adult cells derived from all three germ layers. In contrast, secondary CAMs such as the neuron-glia CAM (Ng-CAM) appear later in development and have more restricted tissue distributions. We have recently determined the structure of Ng-CAM, and other investigators have characterized other CAMs. Most of these cell surface glycoproteins can be grouped into one of two families, one resembling N-CAM and the other resembling L-CAM. N-CAM-related molecules contain segments similar to immunoglobulin domains; they are expressed in a variety of tissues and some have been correlated with disease states, particularly cancer. L-CAM- related molecules differ significantly in structure from those in the N-CAM family and mediate calcium-dependent adhesion. Despite the identification of new CAMs, the number of primary CAMs remain small, supporting the view that the regulation of CAM expression and modulation of CAM activities are as critical to developmental processes as is the specificity of CAM binding. We will now focus our efforts on describing the genomic elements and trans- acting factors involved in the regulation of the expression of N-CAM and L- CAM and on identifying proteins that modulate their activity. We will also characterize the gene for Ng-CAM and assess the binding activity of Ng-CAM relative to that of N-CAM. Regulatory genomic elements will be obtained from bacteriophage clones and cosmid clones and will be assayed with reporter genes in transfected cells and in chimeric chickens and transgenic mice. Protein chemistry, molecular biology, cellular transfection, and immunological techniques will be used to identify trans-acting factors and to analyze molecules that affect CAM binding. Identifying the factors that regulate and influence CAM expression and activity could open the way for understanding basic developmental processes such as induction and differentiation, as well as a variety of pathological conditions including birth defects, tumor onset and metastasis, and degenerative processes in aging.